The overall goal of this project is to assess genetic and immunological factors that contribute to the pathogenesis of neurological disease and to identify therapeutic approaches based on modification of immunological mechanisms. Particular attention is focused on multiple sclerosis (MS), since this disease is thought to have an immunological basis. Both genetic and immunological factors are being examined in patients with well-characterized, clinically definite MS. Genetic aspects of the disease are being examined both in sporadic patients, as well as, members of multiplex MS families that have multiple affected members, and in sets of monozygotic or dizygotic twins that are concordant or discordant for MS. T-cell receptor (TCR) usage has been examined in sets of monozygotic twins, either concordant or discordant for MS. The results of these studies have shown a general skewing of TCR usage, and have demonstrated increasing diversity of the CDR-3 region with progression of disease. Parallel studies are now being conducted in monozygotic twins with other immunological diseases such as insulin-dependent diabetes mellitus. Various forms of immunomodulatory therapy are being examined in the treatment of MS. The cytokine, transforming growth factor-beta2, which has been found to be effective experimentally in the animal model, experimental allergic encephalomyelitis, is now being tested in Phase I studies in patients with active, chronic-progressive MS. The Phase I trial is designed to examine toxicity as a first step in planning larger studies designed to examine efficacy of this treatment. The clinical course and potential treatment of patients with HTLV-I- associated myelopathy/tropical spastic paraparesis (HAM-TSP) is being evaluated. This disease may represent an example of viral-induced immunopathological disease, and consequently, represents in important model disease to study immunological parameters and the effect of immunomodulatory therapies. Preliminary testing of a therapy designed to reduce the number of activated T cells using an antibody to the IL-2 receptor are now under way. The study involves monitoring both immunological and clinical parameters.